TWEAK affects keratinocyte G2/M growth arrest and induces apoptosis through the translocation of the AIF protein to the nucleus

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Sanaa Sabour Alaoui - , INSERM - Institut national de la santé et de la recherche médicale, Université Paris Cité, Chouaib Doukkali University (Autor:in)
  • Valérie Dessirier - , INSERM - Institut national de la santé et de la recherche médicale, Université Paris Cité (Autor:in)
  • Elisabeth de Araujo - , INSERM - Institut national de la santé et de la recherche médicale, Université Paris Cité (Autor:in)
  • Vassilia Ismini Alexaki - , Universität Kreta (Autor:in)
  • Vassiliki Pelekanou - , Universität Kreta (Autor:in)
  • Mustapha Lkhider - , Chouaib Doukkali University (Autor:in)
  • Efstathios N. Stathopoulos - , Universität Kreta (Autor:in)
  • Elias Castanas - , Universität Kreta (Autor:in)
  • Martine Bagot - , INSERM - Institut national de la santé et de la recherche médicale, Université Paris Cité, Hôpital Saint-Louis AP-HP (Autor:in)
  • Armand Bensussan - , INSERM - Institut national de la santé et de la recherche médicale, Université Paris Cité, Hôpital Saint-Louis AP-HP (Autor:in)
  • Andreas Tsapis - , INSERM - Institut national de la santé et de la recherche médicale, Université Paris Cité (Autor:in)

Abstract

The soluble TNF-like weak inducer of apoptosis (TWEAK, TNFSF12) binds to the fibroblast growth factor-inducible 14 receptor (FN14, TNFRSF12A) on the cell membrane and induces multiple biological responses, such as proliferation, migration, differentiation, angiogenesis and apoptosis. Previous reports show that TWEAK, which does not contain a death domain in its cytoplasmic tail, induces the apoptosis of tumor cell lines through the induction of TNFα secretion. TWEAK induces apoptosis in human keratinocytes. Our experiments clearly demonstrate that TWEAK does not induce the secretion of TNFα or TRAIL proteins. The use of specific inhibitors and the absence of procaspase-3 cleavage suggest that the apoptosis of keratinocytes follows a caspase- and cathepsin B-independent pathway. Further investigation showed that TWEAK induces a decrease in the mitochondrial membrane potential of keratinocytes. Confocal microscopy showed that TWEAK induces the cleavage and the translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus, thus initiating caspase-independent apoptosis. Moreover, TWEAK induces FOXO3 and GADD45 expression, cdc2 phosphorylation and cdc2 and cyclinB1 degradation, resulting in the arrest of cell growth at the G2/M phase. Finally, we report that TWEAK and FN14 are normally expressed in the basal layer of the physiological epidermis and are greatly enhanced in benign (psoriasis) and malignant (squamous cell carcinoma) skin pathologies that are characterized by an inflammatory component. TWEAK might play an essential role in skin homeostasis and pathology.

Details

OriginalspracheEnglisch
Aufsatznummere33609
FachzeitschriftPloS one
Jahrgang7
Ausgabenummer3
PublikationsstatusVeröffentlicht - 16 März 2012
Peer-Review-StatusJa
Extern publiziertJa

Externe IDs

PubMed 22438963

Schlagworte

ASJC Scopus Sachgebiete